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PDBsum entry 5mnh
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References listed in PDB file
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Key reference
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Title
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Intriguing role of water in protein-Ligand binding studied by neutron crystallography on trypsin complexes.
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Authors
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J.Schiebel,
R.Gaspari,
T.Wulsdorf,
K.Ngo,
C.Sohn,
T.E.Schrader,
A.Cavalli,
A.Ostermann,
A.Heine,
G.Klebe.
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Ref.
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Nat Commun, 2018,
9,
3559.
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PubMed id
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Abstract
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Hydrogen bonds are key interactions determining protein-ligand binding affinity
and therefore fundamental to any biological process. Unfortunately, explicit
structural information about hydrogen positions and thus H-bonds in
protein-ligand complexes is extremely rare and similarly the important role of
water during binding remains poorly understood. Here, we report on neutron
structures of trypsin determined at very high resolutions ≤1.5 Å in
uncomplexed and inhibited state complemented by X-ray and thermodynamic data and
computer simulations. Our structures show the precise geometry of H-bonds
between protein and the inhibitors N-amidinopiperidine and benzamidine along
with the dynamics of the residual solvation pattern. Prior to binding, the
ligand-free binding pocket is occupied by water molecules characterized by a
paucity of H-bonds and high mobility resulting in an imperfect hydration of the
critical residue Asp189. This phenomenon likely constitutes a key factor fueling
ligand binding via water displacement and helps improving our current view on
water influencing protein-ligand recognition.
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